Designer drug is a term used to describe psychoactivedrugs which are created (or marketed, if they had already existed) to get around existing drug laws by modifying their molecular structures to varying degrees.

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The term originated with law enforcement, but has gained widespread use. The term was originally coined in the 1980s to refer to various heroin like synthetic substances, mostly based on the fentanyl molecule. The term gained widespread popularity when MDMA (ecstasy) experienced a popularity boom in the mid 1980s. In the United States, the Controlled Substances Act was amended with the Controlled Substance Analogue Enforcement of 1986 which attempted to ban designer drugs pre-emptively by making it illegal to manufacture, sell, or possess chemicals which were substantially similar in chemistry and pharmacology to Schedule I or Schedule II drugs. Other countries have dealt with the issue differently. In some, they simply ban new drugs as they become a concern, such as in Germany or Canada. Some countries have gone the opposite direction, such as the United Kingdom and Australia, and enacted sweeping bans based on chemical structure only, making chemicals illegal even before they are created - if a chemical fits a set of rules regarding substitutions and alterations of an already banned drug, it too is banned.

When the term was coined in the 1980s, there were a range of narcotics being sold as heroin on the black market. Many were based on fentanyl or meperidine. One, MPPP, was found in some cases to contain an impurity called MPTP which caused instant and permanent symptoms like Parkinson's disease. Other problems were highly potent fentanyl analogues which were sold as China White and led to many accidental overdoses. Because the government was powerless to prosecute people for these drugs, laws were passed to give the DEA power to emergency schedule chemicals for a year with an optional 6 month extension while gathering evidence to justify permanent scheduling, as well as the analogue laws mentioned previously.

The first time the emergency scheduling power was used was for MDMA. It has subsequently been used for a variety of other drugs including 2C-B, AMT, and BZP. In 2004, a piperazine drug, TFMPP, became the first drug which had been emergency scheduled to be denied permanent scheduling and revert to legal status.

In the late 1990s and early 2000s there was a huge explosion in designer drugs being sold over the internet. The term and concept of "research chemicals" was coined by some marketers of designer drugs (particularly of psychedelic drugs in the tryptamine and phenethylamine family). The idea was that by selling the chemicals as for research rather than human consumption, the intent clause of the U.S. analogue drug laws would be avoided. This was later shown to be faulty logic when the DEA raided multiple suppliers, first JLF Primary Materials, and then multiple vendors several years later in Operation Web Tryp. This process was accelerated greatly when vendors began advertising via search engines like Google by linking their sites to searches on key words such as chemical names and terms like psychedelic or hallucinogen. Widespread discussion of consumptive use and the sources for the chemicals in public forums also drew attention of the media and authorities.

Many substances which were sold as "research chemicals" in this time are hallucinogens and bear a chemical resemblance to common drugs such as psilocybin and mescaline. As with other hallucinogens, these substances are often taken for the purposes of facilitating spiritual processes (see entheogen), mental reflection (see psychedelic) or recreation. Some research chemicals on the market were not psychoactive, but can be used as precursors in the synthesis of other potentially psychoactive substances, for example, 2C-H which could be used to make 2C-B and 2C-I among others. Extensive surveys of structural variations have been conducted by pharmaceutical corporations, universities and independent researchers over the last century, from which some of the presently available research chemicals derive. One particularly notable researcher is Dr. Alexander Shulgin, who presented syntheses and pharmacological explorations of hundreds of substances in the books TiHKAL and PiHKAL (co-authored with Ann Shulgin), and has served as an expert witness for the defense in several court cases against manufacturers of psychoactive drugs.

Most chemical suppliers sold research chemicals in bulk form as powder, not as pills, as selling in pill form would invalidate the claims that they were being sold for non-consumptive research. Active dosages vary widely from substance to substance, ranging from sub-microgram levels to hundreds of milligrams, but while it is critical for the end user to weigh doses with a precision scale, instead of guessing ("eyeballing"), many users did not do this and this led to many emergency room visits and several deaths, which were a prominent factor leading to the emergency scheduling of several substances and eventually Operation Web Tryp. When a chemical increases in popularity, it will often be sold in pill form to reach a wider market. Some of the most popular chemicals are also given street names (like "Foxy" or "Foxy Methoxy" for 5-Meo-DiPT). Once a chemical reaches this kind of popularity, it is usually just a matter of time before it is added to the list of scheduled (regulated) drugs.

Little if any research has been done on the toxicology or pharmacology of most of these drugs. Few, if any, human or animal studies have been done. Unlike better-known drugs like alcohol or marijuana, which have been used by millions of people worldwide, research chemicals are new and may only have been used by a few dozen people for a few months although some drugs such as 2c-b have been used by thousands of people. The safety of research chemicals is untested and due to the recent development of many of them, laws banning or restricting their use have not been developed yet. However, many of the chemicals fall under the various drug analogue legislations in different countries.

In 2004, the US Drug Enforcement Administration raided and shut down several internet based research chemical vendors in an operation called Web Tryp. With help from the authorities in India and China, two chemical manufacturers were also closed. Many other internet based vendors promptly stopped doing business, even though their products are still not scheduled.

Most research chemicals are structural analogues of tryptamines or phenethylamines, but there are also completely unrelated chemicals which are normally considered to be part of the group. It is impossible to determine psychoactivity or other pharmaceutical properties of these chemicals strictly from examining their structure, and many of the substances have common effects whilst structurally different and vice versa. Confusing nomenclature, similar names, and differing naming schemes can all lead to (and is anecdotally known to have led to) potentially hazardous mixups for end users.

TFMPP, 3-Trifluoromethylphenylpiperazine, has the unique distinction of being the only drug to be emergency scheduled into Schedule I and then allowed to become legal because the DEA was unable to justify permanent scheduling